Metabolic adaption of macrophages to heme detoxification in systemic vascular inflammation

巨噬细胞对全身血管炎症中血红素解毒的代谢适应

• 批准号: 10705347
• 负责人: NORBERT LEITINGER
• 金额: $ 51.74万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705347
• 关键词: Atherosclerosis; Biliverdine; Blood Circulation; Blood Vessels; Brain; Brain hemorrhage; Carbon Monoxide; Cardiometabolic Disease; Cell Respiration; Cell Survival; Cells; Cellular Metabolic Process; Chronic; Data; Drug Metabolic Detoxication; Enzymes; Event; Generations; Genetic Diseases; Glucose; Glucosephosphate Dehydrogenase; Glucosephosphate Dehydrogenase Deficiency; Goals; Heme; Hemolysis; Hemorrhage; Immune; Inflammation; Inflammatory; Inherited; Iron; Lead; Link; Lipids; Liver; Malaria; Metabolic; Metabolism; Microglia; Molecular; Mus; Myocardial Infarction; NADP; Oxidative Stress; Oxides; Pathologic; Pathology; Pathway interactions; Patients; Pentosephosphate Pathway; Pharmacology; Phosphogluconate Dehydrogenase; Phospholipids; Physiological; Play; Prevention; Reactive Oxygen Species; Resolution; Risk; Role; Rupture; Sepsis; Sickle Cell Anemia; Spleen; Stress; Stroke; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Trauma; enzyme pathway; heme oxygenase-1; improved; iron (III) reductase; iron metabolism; macrophage; monocyte; mouse model; new therapeutic target; oxidation; prevent; response; six transmembrane epithelial antigen of the prostate 3; treatment strategy; vascular inflammation

SUMMARY Hemolysis accompanies many pathologies including trauma, sepsis, hemorrhagic stroke, malaria, and genetic disorders such as sickle cell disease (SCD) and glucose-6-phosphate dehydrogenase (G6PD) deficiency. The release of free heme into the circulation promotes numerous vascular pathologies and therefore, efficient heme clearance and detoxification is necessary to prevent sustained tissue damage. Chronic hemolysis results in vascular inflammation driven by free heme, accompanied by oxidative tissue damage, which may lead to generation of oxidized phospholipids that are implicated in atherosclerosis and cardiometabolic disease complications. Here, we will test the overall hypothesis that in settings of hemolytic stress, G6PD deficiency becomes increasingly detrimental due to dysfunctional metabolic adaptation, and that metabolic adaptation of macrophages and monocytes is essential for the resolution of hemorrhage in SCD. In specific aim 1 we will test the hypothesis that metabolic adaptation in macrophages is necessary for efficient heme-clearance and cell survival and to determine the molecular mechanisms that regulate the metabolic shift to the PPP in the context of hemolysis. We will also examine the consequences of insufficient heme detoxification for cell survival and lipid oxidation in systemic hemolysis in G6PD and Steap3 transgenic mice and test the hypothesis that the phosphofructokinase PBFKB3 is the target for CO to activate the PPP. In specific aim 2 we will demonstrate the significance of metabolic adaptation to heme detoxification in SCD. We will examine metabolic shift in murine models of SCD and characterize blood monocyte metabolic state in SCD patients. These studies will identify novel therapeutic targets to improve heme detoxification and ameliorate heme-induced oxidative tissue damage.

总结 溶血伴随许多病理，包括创伤、败血症、出血性中风、疟疾和遗传性溶血。 疾病如镰状细胞病（SCD）和葡萄糖-6-磷酸脱氢酶（G6 PD）缺乏。的 游离血红素释放到循环中促进了许多血管病变 清除和解毒对于防止持续的组织损伤是必要的。慢性溶血导致 由游离血红素驱动的血管炎症，伴有氧化性组织损伤，这可能导致 与动脉粥样硬化和心脏代谢疾病有关的氧化磷脂的产生 并发症在这里，我们将测试的整体假设，即在设置溶血性应激，G6 PD缺乏症， 由于代谢适应功能失调而变得越来越有害， 巨噬细胞和单核细胞对于SCD中出血的消退是必需的。 在具体目标1中，我们将检验巨噬细胞中的代谢适应对于有效的 血红素清除和细胞存活，并确定调节代谢转变的分子机制 在溶血的情况下与PPP相关联。我们还将研究血红素解毒不足的后果 在G6 PD和Steap 3转基因小鼠中进行系统性溶血中的细胞存活和脂质氧化，并测试 假设磷酸果糖激酶PBFKB 3是CO激活PPP的靶点。在具体目标2中， 将证明SCD中血红素解毒的代谢适应的重要性。我们将研究 在SCD的鼠模型中的代谢变化和表征SCD患者中的血液单核细胞代谢状态。 这些研究将确定新的治疗靶点，以改善血红素解毒和改善血红素诱导的 氧化性组织损伤